LSD1 promotes oncogenesis via H3K9 demethylation-mediated cell cycle gene expression and cellular senescence inhibition

Histone H3 lysine-9 methylation (H3K9me) is essential for retinoblastoma protein (RB)-mediated heterochromatin formation, epigenetic silencing of S-phase genes and permanent cell cycle arrest or cellular senescence. Besides as an H3K4me demethylase, lysine-specific demethylase 1 (LSD1) has also been shown to promote H3K9 demethylation. However, it is unclear whether LSD1 plays any roles in regulating cell cycle entry and senescence. Here we demonstrate that genetic depletion or pharmacological inhibition of LSD1 triggers G1 arrest and cellular senescence. Genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) analysis reveal that the binding sites of LSD1 significantly overlaps with those bound by the S-phase gene transcription factor E2F1. Gene ontology (GO) analysis demonstrates that a large portion of E2F1 and LSD1 co-targeted genes are involved in cell cycle and proliferation. Further analyses show that depletion of LSD1 not only inhibits expression of the LSD1-E2F1 co-target genes, but also decreases the level of H3K9me2, but not H3K4me2 in those loci. Furthermore, the enzymatic activity of LSD1 is essential for H3K9me2 demethylation at cell cycle gene loci. Notably, co-treatment of chemotherapeutic agent camptothecin (CPT) enhanced LSD1 inhibitor-induced senescence and growth inhibition of cancer cells in vitro and in mice. Our data reveal LSD1 as a molecular rheostat regulating selective H3K9 demethylation at cell cycle gene loci, thereby representing a key event in oncogenesis and a viable target for cancer therapy.

Dataset features

Information

Specifications

Application:	ChIP-seq analysis
Number of samples:	5
Release date:	Jan 29 2017
Last update date:	Oct 18 2018
Access:	Public
Diseases:	Neoplasms, Retinoblastoma
Chemicals:	Camptothecin
Dataset link	LSD1 promotes oncogenesis via H3K9 demethylation-mediated cell cycle gene expression and cellular senescence inhibition

Experimental Protocol

Examination of 2 LSD1 and E2F1 in cell lines

Repositories

GEO

GSE77448

ENA

SRP069151

BioProject

PRJNA310349

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Contact

Zhenqing Ye